Major Impacts of the Pandemic—and Future Implications for the Biopharmaceutical Industry

By Lynne Ensor

The events of the past two years have made a profound impact on biopharmaceutical companies and every cog in the wheel of our industry. Internally, firms were forced to make radical shifts in operational procedures. Externally, regulatory agencies faced their own challenges, and suppliers and the supply chain worldwide suffered from massive disruption.

That said, countless positive outcomes have already emerged from the chaos. Most prominent, of course, are the vaccines that were developed and distributed with unprecedented speed to save lives and alleviate the public health emergency. But many epiphanies arose from the necessity to do things differently.

What have we learned? What new approaches will be carried forward? What steps can companies take to prepare for a return to business “as usual”? This article explores those questions, focusing on five key aspects beginning with platform technologies.

The acceleration of platform technologies

Platform technology describes a process which can be used for the manufacture of a group of related products in a defined production system. The manufacture of mRNA vaccines, which had been developing over decades, is an example of a current platform technology that rapidly accelerated as the vaccines were employed effectively to combat COVID-19.

Although mRNA vaccines were originally being targeted to illnesses such as seasonal flu, companies quickly pivoted their platforms to direct them against SARS-CoV-2, often engaging in unprecedented collaborations.

By enabling that rapid adaptation while still resulting in reproducible and compliant manufacturing, platform technology could well be the wave of the future.

• Platform technologies allow for pivots to slightly modified targets, as any target organism evolves against human defenses or therapies.
• Once the platform technology is well defined, regulatory scrutiny could primarily focus on the specific target. This would enable regulators to quickly review scientific data and provide assessments against those specific targets, potentially leading to a more efficient approval process. Regulators would not need to reassess the platform technology in depth if it has been previously approved for the manufacture of another related product.
• Platform technology also holds great potential for targeting rare diseases.
• By enabling more efficient product development, these technologies are likely to be critical in providing quick response to future pandemic threats.

In short, the pandemic will likely allow us to assess the data compiled from the use of these technologies for years to come to determine their potential for benefitting global health.

The unprecedented prevalence of emergency use authorization

In the U.S., the COVID pandemic allowed for the trigger of the Emergency Use Authorization (EUA) process according to the Food, Drug, and Cosmetic Act (FD&C Act). First established by Congress in 2004, the EUA process allows the U.S. Food and Drug Administration (FDA) power to authorize products for temporary use as emergency medical countermeasures against threats to public health and safety.

Until recently, EUAs were seldom submitted and authorized by the FDA, a level that appeared to align with their original intent. However, during the pandemic, this process has been used for over 600 products in less than two years, compared to less than 40 in the previous 16 years. These recent authorizations include COVID vaccines, drugs, and biological therapeutic products, as well as a wide range of Personal Protective Equipment (PPE), diagnostics, and other medical consumables.

The big question now is this: When will the declaration of the public health emergency, which triggered allowance for the large volume of recent EUAs, be terminated? The federal government is under tremendous political pressure to get the country moving toward life as it was pre-pandemic. One aspect of that demand is to terminate the public health emergency and thus, the availability of the EUA process to the FDA to combat the COVID pandemic. Phasing out the EUA would in turn trigger the necessity to potentially convert those EUA products to full FDA approval. Any product granted EUA status will need to undergo the typical FDA approval process before it can be distributed in the United States, if that hasn’t already occurred.

There are grave concerns within the pharmaceutical industry about taking this step. To begin with, the details from regulators for the transition of certain products to full approval are not entirely clear at this point. Further, FDA resources have been extremely strained during the pandemic. Organized processes and regulatory resources are necessary to support conversion of EUAs to fully approved products, creating additional challenges for overburdened personnel. Lastly, if a significant number of products are not successfully transitioned from EUA to full FDA approval, there could be resulting supply shortages for patients as the pandemic continues if the lifting of the public health emergency is not optimally timed.

Stepping back to take the long view, however, there are silver linings, beginning with significant learning about the EUA process. What worked well and what did not during the public health emergency? Some of the regulatory actions taken could be utilized in the future, such as revising or accelerating the FDA’s approval process based on the learnings from pandemic EUAs.

Clearly, the pandemic highlighted the opportunity for improved preparedness planning in the U.S. at both the federal and state level since coordination might not have been optimal during this period. This opportunity could very well encompass a reexamination of the FDA’s organizational placement and leadership. The pandemic created unanticipated visibility and demands on the FDA as a byproduct, leading to the need for flexible, bipartisan, and most importantly, scientific-based responses to be made by the agency. Measures could be taken to insulate the agency from political pressures – for example, potentially establishing leadership term limits.

The impact on regulatory inspection

Beginning in the early spring of 2020, the FDA postponed many foreign and domestic inspections due to travel restrictions and general health advisories related to the COVID pandemic, prioritizing those considered mission-critical. Regulators then pivoted to performing remote facility assessment when deemed appropriate. By midyear 2021, the FDA had begun the transition back to standard operations for domestic inspections, but continued to be hindered by travel challenges as the SARS-CoV-2 virus evolved and its mutants caused infection spikes in various regions.

However, regulators were still hindered in conducting foreign inspections by travel constraints, exacerbated by emerging variants of SARS-CoV-2, thus delaying restart of inspections as intended. By the spring of 2022, the FDA was preparing to perform domestic inspections at pre-pandemic levels, but foreign inspections remain a challenge. Mission-critical inspections are being prioritized, but some still are impossible in certain regions, such as China.

Currently, there are four types of facility assessment and inspection tools to assess Current Good Manufacturing Practices (CGMP) available to the FDA.

• Remote records assessment. This is a desk-based audit performed of the records provided by firms to the regulator requested under §704(a)(4) of the Food, Drug & Cosmetic Act. This allows for a records request in advance of or in lieu of an inspection, focusing on risk-based considerations of the facility. This records request is being used to assess the capability of the facility and its quality systems to perform the manufacturing operations indicated.
• Remote interactive evaluation (RIE). This typically involves assessment of documentation provided by the firm to the FDA in conjunction with a virtual facility evaluation, where subject-matter experts are available to interact virtually with regulators and visual technologies may be employed to observe the manufacturing facility and staff.
• On-site inspection. This typical inspection format is still an option, although challenges persist in performing them, as described.
• Hybrid inspection. This approach could involve performing an initial records assessment or RIE, followed up with an on-site inspection as travel allows or post-approval. This is very much akin to how CDER-regulated biologics are typically assessed by FDA, where the CMC assessor leads the inspection of either the drug substance or drug product after being familiar with the documentation in Biologics License Application from their assessment. This allows for the inspection of those products to be performed in a risk-based manner, focusing on high-risk areas of concern noted in the BLA, at the facility, or where inconsistencies between the two are identified.

As remote options have been developed by regulators, some confusion has emerged due to the way they are referenced, as acronyms have evolved during the pandemic. Compounding this confusion is that various global regulators may have differing expectations and methods for conducting these options, making it challenging to provide optimal support and outcomes for all of them. Recently, U.S. regulators appear to be broadening the reliance on Mutual Recognition Agreements or information from other global regulators as the pandemic continues.

In any case, the pandemic highlighted the need to invest in enhancing virtual support tools so that regulators may continue to work remotely when appropriate and most efficiently. Going forward, we will see which of these options for facility assessment and/or inspection will be used in the long term or even permanently. There may be the need for legislative updates to the 1953 updates to the FD&C Act if virtual facility assessment options can be considered a replacement for an on-site, in-person regulatory inspection, when a regulator physically enters a facility.

This flow chart depicts the risk-assessment process used by the FDA/ CDER/Office of Pharmaceutical Quality to determine what type of facility assessment will be used for a Pre-Approval Inspection (PAI) or Pre-Licensing Inspection (PLI) during the pandemic. The risk-based decision tree considers information about the facility that can help determine whether an on-site inspection must be performed. According to recent agency communications, this process has allowed regulators to make strides in meeting surveillance facility assessment and inspection goals.

Regulators have been developing and utilizing risk-based approaches that take into consideration the product and site risk and criticality. It follows that sites and product that have demonstrated a strong quality management system in the past could be more likely to avert an on-site inspection. First impressions during an on-site inspection are now even more important for a positive reputation and to demonstrate a sound quality management system with regulators.

Many firms may have increased their own use of virtual support, including more reliance on electronic documentation, especially to support remote quality review of manufactured batches. In such cases, they need to ensure that any changes to their IT infrastructure meet regulatory expectations for secure document storage. Additionally, liability issues might have arisen related to the health of their workers, determining their vaccination status, and whether any OSHA-reportable issues occurred. These adjustments might have caused unintended gaps in compliance and manufacturing challenges, which regulators will identify once they are performing on-site inspections at pre-pandemic levels.

Some facilities quickly pivoted to increase capacities or change their manufacturing lines to support the production of COVID-related products or other in-demand medical products. The pandemic highlighted the reliance on contract manufacturing organizations, especially for products being developed quickly in response to the pandemic, requiring scale-up options to manufacture at a global supply level.

The pandemic also brought to light the importance of business continuity planning to allow for ongoing manufacturing and product availability. Contingencies might include determining which on-site activities are essential and which can be performed remotely, postponed, or even cancelled, and ensuring continuity in the face of employee illness or exposure to the virus.

Conclusion

The world has forever been impacted by the pandemic. The impact on our industry will not be fully understood for years to come. No one really knows how many of the regulatory changes allowed during the public health emergency will be used or adapted in the future to improve the efficiency of the drug approval process. Lessons learned about supply chain vulnerabilities during the pandemic will require continual analysis in the effort to ensure the domestic availability of APIs and medical products.

In any event, it is highly likely that these analyses will reveal the viability of both regulatory and industry improvements in normal operations, and for rapid, coordinated, effective response in the event of a future pandemic.

This is an excerpt from an article that appeared in American Pharmaceutical Review on August 1, 2022. To read the complete article including references, click here.